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Proc Natl Acad Sci U S A. Jun 14, 2005; 102(24): 8603–8608.
Published online Jun 7, 2005. doi:  10.1073/pnas.0503072102
PMCID: PMC1150839
Genetics

Global and Hox-specific roles for the MLL1 methyltransferase

Abstract

The mixed-lineage leukemia (MLL1/ALL-1/HRX) histone methyltransferase is involved in the epigenetic maintenance of transcriptional memory and the pathogenesis of human leukemias. To understand its role in cell type specification, we determined the human genomic binding sites of MLL1. We found that MLL1 functions as a human equivalent of yeast Set1. Like Set1, MLL1 localizes with RNA polymerase II (Pol II) to the 5′ end of actively transcribed genes, where histone H3 lysine 4 trimethylation occurs. Consistent with this global role in transcription, MLL1 also localizes to microRNA (miRNA) loci that are involved in leukemia and hematopoiesis. In contrast to the 5′ proximal binding behavior at most protein-coding genes, MLL1 occupies an extensive domain within a transcriptionally active region of the HoxA cluster. The ability of MLL1 to serve as a start site-specific global transcriptional regulator and to participate in larger chromatin domains at the Hox genes reveals dual roles for MLL1 in maintenance of cellular identity.

Keywords: ALL-1, histone methyltransferase, Set1, trithorax, microRNA

Eukaryotic gene expression is controlled largely by modification of chromatin structure through the enzymatic action of transcriptional regulators. These modifications include histone acetylation, deacetylation, phosphorylation, ubiquitination, and ATP-dependent chromatin remodeling (1, 2). It has been proposed that these modifications serve as molecular “marks” to produce a histone code that can be read by downstream proteins. Orchestrated deposition of these histone marks can drastically alter binding of the transcriptional machinery to effect transcriptional output.

Histone methylation is intimately linked to the epigenetic inheritance of transcriptionally permissive or prohibitive chromatin states. Recently, methylation of histone H3 at lysine 4 (H3-K4) has been shown to be associated with an active chromatin structure that is permissive to transcription (36). The Saccharomyces cerevisiae Set1 protein was shown to possess H3-K4 methyltransferase activity and provide a highly localized mark of recent transcriptional activity (5, 712). A distinguishing feature of Set1 is the ability to localize with RNA polymerase II (Pol II) immediately downstream to the transcriptional start sites of highly expressed genes (5, 12). Another hallmark of Set1 is the ability to catalyze the trimethylation of histone H3 at this location. This trimethyl mark on the 5′-coding region of yeast genes can remain long after transcription has ceased. Whereas H3-K4 dimethylation is spread throughout the genome, H3-K4 trimethylation is enriched immediately downstream of the transcription start site. The location and persistence of the H3-K4 trimethyl mark suggests that Set1 catalyzed H3-K4 trimethylation provides a molecular memory of the active gene state in a specific cellular environment.

Multicellular eukaryotes require that distinct cellular subgroups assume a specialized function and actively maintain a memory of that cellular identity. A mammalian system similar to the yeast Set1/H3-K4 methylation system is thought to fulfill this role. Although proteins homologous to Set1 have been identified in humans [hSet1, MLL1 (mixed-lineage leukemia 1), MLL2, ALR-1, and HALR], it is not clear which of these proteins behaves as the equivalent of Set1. MLL1 is a strong candidate because it is known to possess H3-K4 methyltransferase activity and is involved in the maintenance of hematopoietic developmental states (1316). Because MLL1 has also been shown to interact with components of the basal transcription apparatus and human equivalents of the yeast Set1 complex (14, 17, 18), we focused on human MLL1 as a potential functional analog of yeast Set1.

Chromosomal translocations that fuse the MLL1 methyltransferase to one of >50 known partners are correlated with the occurrence of aggressive myeloid and lymphoid leukemias in infants and in patients with therapy-associated leukemia (19, 20). MLL1 is a mammalian member of the Drosophila trithorax group (Trx-G) proteins, which are responsible for maintenance of Hox transcriptional states during development. Trx-G proteins serve to maintain genes in the active state, whereas polycomb group (Pc-G) proteins are associated with stable repression (21). Evidence suggests that native MLL1 regulates Hox genes in hematopoietic cells to establish cellular identity (15, 16, 22). Disruption of MLL1 function by chromosomal translocation results in Hox misregulation coupled with the onset of leukemic phenotypes (2224). Endogenous MLL1 regulates transcription at least in part by modifying chromatin structure by means of H3-K4 methylation (12, 13). This histone methyltransferase activity is endowed by the SET [Su(var) 3–9, enhancer of zeste, trithorax] domain of MLL1, which is homologous to the Drosophila trithorax and yeast Set1 proteins.

Although MLL1 is known to catalyze H3-K4 methylation of two genes (HoxA9 and HoxC8), it is not known whether MLL1 can act as a global regulator of actively transcribed genes. Inadequate knowledge of the target genes that MLL1 regulates has also hindered efforts to understand its non-Hox-related functions. To determine the target genes and transcriptional behaviors of MLL1, we performed genome-wide location analysis using a human promoter DNA microarray. We also determined MLL1 occupancy across a subset of diverse genes within regions extending upstream and downstream of their proximal promoters. We show that MLL1 acts as a functional human equivalent of yeast Set1. MLL1 binds near the transcriptional start sites of most Pol II occupied genes and this binding is correlated with gene expression. We also determined the genomic location of H3-K4 methylation across human promoters and found that MLL1 occupancy is strongly correlated with H3-K4 trimethylation. Furthermore, the binding of MLL1 to a large actively transcribed region of the HoxA cluster reveals a very different binding behavior involved in the maintenance of active transcriptional domains.

Materials and Methods

Antibodies. Affinity-purified rabbit polyclonal anti-MLL1 antibody 173 and 170 were described (14). Control polyclonal rabbit IgG antibody was obtained from Upstate Biotechnology (Lake Placid, NY). Anti-Pol II monoclonal antibody 8WG16 was directed against the highly conserved Pol II carboxyl-terminal domain (CTD). H3-K4 trimethyl antibody was obtained from Abcam (ab6002). Histone H3 CTD antibody (ab1791) was obtained from Abcam (Cambridge, MA).

Genome-Wide Location Analysis. The protocol described here was adapted from ref. 25. Briefly, 2.0 × 108 U937 cells were fixed with a 1% final concentration of formaldehyde for 20 min at room temperature, harvested, and rinsed with 1× PBS. The resultant cell pellet was sonicated, and DNA fragments were enriched by immunoprecipitation (IP) with a factor-specific antibody. After reversal of the crosslinking, the enriched DNA was amplified by using ligation-mediated PCR (LM-PCR) and then fluorescently labeled by using high-concentration Klenow polymerase and a dNTP fluorophore. A sample of reference DNA not enriched by IP was subjected to LM-PCR and labeled with a different fluorophore. Both IP-enriched and unenriched pools of labeled DNA were hybridized to the human promoter array. Each experiment was performed independently in triplicate.

Human 19K DNA Microarray. Design and quality control for the human 13K array has been described (26). Expansion of the 13K (13,000 features) to 19K (19,000 features) array was performed as follows. We collated all genes from The National Center for Biotechnology Information (NCBI) Reference Sequence (Ref-Seq), Ensembl (www.ensembl.org), and Mammalian Gene Collection (MGC; http://mgc.nci.nih.gov) from build 34 of the human genome sequence. Primers were designed against transcription start sites that were included in at least two of the three databases. Proximal promoter features were produced by representing (i) all genes mismapped in the original NCBI build 22 (April, 2001) and (ii) all genes predicted to encode transcriptional regulators as described in Gene Ontology (GO) annotation. The promoter regions spanned 750-bp upstream to 250-bp downstream of the consensus transcription start sites. DNA representing regions of base pairs -3,775 to -2,625, -2,775 to -1,625, -1,775 to -625, -775 to +375, +225 to +1,375, and +1,225 to +2,375 relative to the transcription start site (+1) of 276 diverse genes was also included. A total of 175 microRNA (miRNA) loci containing regions -3,500 to -2,500, -2,500 to -1,500, 1,500 to -500, and -500 to +500 relative to each miRNA hairpin were included. For control normalization, we identified the largest gaps between all predicted genes and designed 5 × 1-kb probes to each of the largest 143 of these gaps (all >1.6 Mb). Of these regions, 623 primer pairs were found. All sequences are ≥800 kb from the nearest gene. Binding data from these intergenic control probes were used to normalize the array data and to estimate the significance of binding ratios for all other probes.

Comparing Location and Expression Data. We used Affymetrix (Santa Clara, CA) expression data from the novartis (version 2) data set (27). Data from replicate tissue samples were averaged, and expression ratios were generated by dividing each value by the row-wise average. The data were converted to log base 2 and normalized so that the column- and row-wise medians were 0. Data for genes represented by multiple probes were averaged giving 12,847 unique genes. The genes were ordered with a one-dimensional self-organizing map and then clustered by using average-linkage hierarchical clustering (28). We isolated binding data for the 10,223 probes confirmed to correspond to proximal promoters (3′ end no more than 500 bp from the transcription start site). For genes represented by multiple probes, we selected the probe with the most significant P value (9,336 unique genes). This analysis gave 6,131 genes for which we had both binding and expression data. Binding events were scored for MLL1, Pol II, and histone H3 trimethyl K4 at the P < 0.001 confidence level.

Gene-Specific Chromatin IP (ChIP) Analysis. Chromatin obtained from 5 × 106 crosslinked U937 cells was used for each ChIP. ChIP analysis was adapted from ref. 25 by using rabbit IgG, Pol II, MLL1, and H3-K4 trimethyl antibodies, as described above. After reversal of crosslinks and DNA isolation, samples were subjected to PCR analysis using primers within the proximal promoter region (base pairs +1 to +250) of Meis1, HoxA11, and HoxB13. Primers against the upstream region (base pairs -750 to -500) of α-actin were used as control.

Results

Genome-Wide Distribution of MLL1. Our interest in determining whether MLL1 acts as a Hox-specific regulator or a Set1-like global regulator led us to identify the genomic binding sites for MLL1 in human. A ChIP-DNA microarray (Genome-wide location analysis or ChIP-chip) approach was used with monocytic U937 cells (Fig. 1; all data associated with this research along with detailed protocols are available from the authors upon request). We produced a DNA microarray containing human proximal promoter regions and noncoding regions of the genome. By using a stringent selection criteria of P < 0.001, we found that MLL1 occupies 5,186 targets in promonocytic U937 cells, which accounts for 38% of the promoters on the microarray. Location analysis with a second MLL1 antibody directed against a different epitope identified essentially the same set of target genes (93% overlap; data not shown). The observation that MLL1 is associated with a substantial fraction of human promoters suggests that MLL1 has a global role in transcription.

Fig. 1.
Identification of MLL1 and Pol II bound regions. (a–c) Single-array intensities of DNA fragments obtained from MLL1 (a), Pol II (b), and IgG control (c) ChIPs plotted against whole-cell extract (WCE) control intensities. Red lines represent confidence ...

The large number of binding sites for MLL1 prompted us to determine whether MLL1 occupancy coincides with RNA Pol II. Pol II was found to bind 5,428 genomic elements, or 29% of the features on the array by using an anti-Pol II CTD antibody. The overlap between MLL1 and Pol II was highly significant, where MLL1 was found to bind to 90% of Pol II occupied regions (Fig. 1d). To determine whether MLL1 cooccupancy with Pol II was cell-specific, we determined the binding characteristics of MLL1 and Pol II in cultured lymphoblasts. MLL1 was found to cooccupy most Pol II bound genes in Jurkat cells, thus indicating that MLL1 can serve as a general regulator in multiple cell types of the hematopoietic lineage (data not shown).

Genomic Distribution of the H3-K4 Trimethyl Mark. Methylation of H3-K4 was first described in S. cerevisiae, where the Set1 protein enzymatically modifies histone H3 to provide a highly localized mark of recent transcriptional activity. In S. cerevisiae, dimethylation of H3-K4 is uniform throughout the genome, whereas trimethylation of H3-K4 is localized to the regions immediately 3′ to transcription start sites (35, 12). This H3-K4 trimethylation is associated with genes that are bound by Set1 and have undergone recent transcriptional activation. To determine whether MLL1 binding correlates with H3-K4 trimethylation, we used location analysis to determine the genomic distribution of the H3-K4 trimethyl mark. We found the H3-K4 trimethyl mark enriched at 5,672 genomic regions (Fig. 2a). This extensive presence of H3-K4 trimethylation corresponds to 41% of the represented microarray promoters. The coincidence of MLL1 binding and the H3-K4 trimethyl mark is nearly total, with 92% of MLL1 occupied regions containing the H3-K4 trimethyl modification (Fig. 2b). Confirmation of MLL1 associated H3-K4 trimethylation was demonstrated by conventional ChIP analysis (Fig. 2c). Localization of Pol II, MLL1, and H3-K4 trimethylation to the proximal Meis1 and HoxA11 promoters, but not to the proximal HoxB13 promoter or upstream region of the α-actin gene, recapitulated the genomic occupancy discovered by microarray analysis. These results suggest that MLL1 is responsible for deposition of the H3-K4 trimethyl mark across a large portion of active promoters.

Fig. 2.
Genomic location of H3-K4 trimethylation. (a) Single-array intensities of DNA fragments enriched by ChIP using anti-H3-K4 trimethylation antibody in U937 cells versus anti-histone H3 immunoprecipitate. Red lines represent confidence thresholds of 0.001, ...

Binding Characteristics of MLL1, Pol II, and H3-K4 Trimethylation. Set1 is recruited to a discrete location within the mRNA-coding regions of actively transcribed genes in S. cerevisiae. This localization is immediately downstream of the transcription start site and corresponds with Pol II binding and H3-K4 trimethylation. To determine whether MLL1 binds at or near the transcription start site, we interrogated 276 genes that were tiled in 1-kb fragments from base pairs -3,775 to + 2,375 in relation to the consensus transcription start site (Fig. 3a). Genes within the HoxA–D clusters were included as well as genes involved in cell cycle regulation, hematopoiesis, immune response, liver homeostasis, and other functions. Similar to yeast Set1, we found that both MLL1 and H3-K4 trimethylation were highly enriched at the transcription start sites and 5′ regions of most genes. Pol II binding was also highly enriched at the transcription start sites of these genes but was not as pronounced beyond the transcription start site (Fig. 3b). This behavior is likely because the Pol II antibody maintains a higher affinity for the unphosphorylated CTD in human cells, whereas yeast Set1 preferentially binds the Ser-5-phosphorylated CTD that is associated with transcriptional initiation. These results are consistent with Set1 binding behavior in S. cerevisiae and confirm our finding that MLL1 binding correlates with H3-K4 trimethylation and Pol II occupancy.

Fig. 3.
Binding behavior of MLL1, Pol II, and H3-K4 trimethylation. (a) Schematic representation of probe sequences used for each of the 276 profiled genes. Overlapping probes in relation to the transcription start site are as follows: 1, -3,775 to -2,625; 2, ...

The extensive overlap of MLL1 and Pol II binding prompted us to determine whether MLL1 binding correlates with high levels of gene expression. To assess this relationship, we examined expression data from multiple human cell lines and tissues. The relative mRNA expression levels from blood, brain, endocrine, and other tissues revealed distinct clusters of highly expressed genes in each tissue (Fig. 4). Alignment of MLL1 and Pol II location data shows that binding of both proteins is correlated with high levels of expression in the monocytic/myeloid cells within the blood subcategory. These findings are in exact agreement with our binding data because genome-wide location analysis was performed in U937 monocytic cells. Also, a striking reduction in MLL1/Pol II binding is seen within highly expressed clusters that define brain and nonhematopoietic tissue. Together, these findings show that MLL1 binds with Pol II at highly expressed genes in a manner similar to yeast Set1.

Fig. 4.
Correlation of MLL1 binding and gene transcription. (Left) Enriched promoter regions obtained from genome-wide location analysis of MLL1, Pol II, and H3-K4 trimethyl in U937 cells are aligned for each individual gene. Blue dashes indicate a positive binding ...

MLL1 Associates with miRNAs Involved in Cancer and Hematopoiesis. Global transcription involves the regulation of both protein-coding and noncoding genes within a given cell type. miRNAs are a class of noncoding RNA species thought to regulate tissue-specific transcriptional programs throughout development (2931). We tiled 175 miRNA genes, including regions 4 kb upstream to detect transcription factor binding events that directly regulate their transcription. Because Pol II has been shown to transcribe these genes (32), we expected that miRNAs important for hematopoietic function would be bound by MLL1 and, correspondingly, H3-K4 trimethylated. Indeed, we found extensive binding of MLL1 and H3-K4 trimethylation at multiple miRNA loci (see Table 1, which is published as supporting information on the PNAS web site). MLL1 was found to bind mir-142, a miRNA known to modulate hematopoietic differentiation (33). Misregulation of miRNA loci is also known to be correlated with leukemias and other forms of cancer (34, 35). We found that MLL1 localizes to a cluster of miRNAs involved in follicular lymphoma (mir-17/18/19a/20/19b-1/92–1 cluster) (30). MLL1 also binds miRNA species (mir-15b and mir-16–2 cluster) that are nearly identical to those associated with chronic lymphocytic leukemia (mir-15a and mir-16–1 cluster) (31). These findings suggest how misregulation of miRNAs by chromatin modifiers such as MLL1 in tumor cells could have profound effects on differentiation and the progression of cancer.

Extensive MLL1 Binding Throughout an Active Hox Domain. MLL1, Pol II, and H3-K4 trimethyl marks localize to a region encompassing the transcription start site for most genes. However, binding events within some genes occur in regions considerably upstream and downstream of the transcription start sites. This unexpected binding behavior was investigated to determine which genes were extensively bound by MLL1 and, correspondingly, H3-K4 trimethylated. Inspection of the gene identities reveals these unique binding events exist primarily within the late HoxA cluster (HoxA7, HoxA9, HoxA10, HoxA11, and HoxA13). The Hox proteins are homeodomain-containing transcription factors that are responsible for maintaining segmental and developmental identity in multiple organisms. Colinear regulation of these Hox genes by members of the trithorax and polycomb group proteins is essential for establishment and maintenance of appropriate cellular identity (36). Coincident with this developmental role, Hox genes are frequently misregulated in hematopoietic cancers. Revealing a dual behavior in transcriptional regulation, MLL1 occupies the genome far upstream (-3,775 bp) and downstream (+2,250 bp) of individual Hox genes within the HoxA cluster but only near the transcription start site of other genes such as the E2F family of transcription factors (Fig. 5). MLL1 localizes to large regions encompassing HoxA1 and the 5′ HoxA subcluster including HoxA7, HoxA9, HoxA10, HoxA11, and HoxA13 (Fig. 5). Binding to these genes is consistent with the high expression level of the late HoxA cluster in U937 cells (37), suggesting that MLL1 forms or maintains a domain of active gene expression within this region. The location of MLL1 binding events correlates with extensive and overlapping regions of H3-K4 trimethylation (Fig. 5). Interestingly, MLL1 also localizes extensively to the Meis1 gene, which is consistently overexpressed in MLL-rearranged leukemias along with HoxA9 and HoxA10 (24, 3841). Thus, our findings implicate MLL1 as a direct regulator of these hallmark leukemia-associated genes and suggest this regulation occurs through chromatin domains (Fig. 5).

Fig. 5.
Hox-specific binding profile of MLL1. (a) Schematic representation of the 130 Kb HoxA cluster region on chromosome 7p15.2. Binding events at P < 0.001 for MLL1 (blue rectangle) and H3-K4 trimethylation (red rectangle) are shown for each individual ...

Summary

Studies in yeast have begun to shed light on the fundamental mechanisms of transcriptional based molecular memory through modification of chromatin structure. Although it is believed that similar mechanisms take place in humans to maintain differentiated cellular states, it is not clear which proteins are directly responsible. Here, we show that MLL1 performs strikingly similar functions in humans as Set1 performs in yeast. The occupancy of MLL1 at the start sites of actively transcribed genes recapitulates Set1 action. We determined the genomic location of H3-K4 trimethylation in human cells and found this modification enriched at transcriptionally active genes. The overlap of MLL1 binding and H3-K4 trimethylation reinforces the role of MLL1 as a positive, global regulator of gene transcription. Evidence supporting this general role for MLL1 includes the presence of TFIID components and human equivalents of the yeast Set1 complex within biochemically purified MLL1 complexes (14, 18). The identification of other trithorax group proteins as components of generally acting ATP-dependent chromatin remodeling complexes is consistent with MLL1 functioning as a general transcription factor. This global role of MLL1 in regulating protein-coding genes and miRNAs is fundamentally different from the proposed Hox-specific role given to MLL1 and instead suggests a wide and integral role for MLL1 in gene expression.

We have shown that MLL1 can localize to extended regions of the HoxA cluster coincident with the H3-K4 trimethyl mark. The extensive binding to hallmark leukemia genes within this region suggests how disruption of MLL1 function contributes to hematopoietic cancers. Proviral integrations that induce B cell leukemia also target the same late HoxA region that MLL1 occupies (42). This indicates that a unique HoxA chromatin structure facilitated by MLL1 is integral to proper hematopoietic differentiation and that disruption by MLL1 translocation or viral integration can contribute to a leukemic phenotype. The ability of MLL1 to form active chromatin domains encompassing genes that are important for cellular identity underscores the severe consequences of disrupting MLL1 function in human leukemias and provides insight into how epigenetic gene regulation is controlled.

Supplementary Material

Supporting Table:

Acknowledgments

We thank T. Lee for critical reading of the manuscript, E. Herbolsheimer for computational support, the Whitehead Institute Bioinformatics Group for probe design, and the Whitehead Institute Microarray Facility for DNA microarray production. This work was supported by the Cancer Research Institute, an Amgen Fellowship grant of the Life Sciences Research Foundation, and grants from the National Institutes of Health.

Notes

Author contributions: M.G.G., E.C., and R.A.Y. designed research; M.G.G. performed research; M.G.G., R.G.J., B.C., T.N., C.M.C., and E.C. contributed new reagents/analytic tools; M.G.G. and R.G.J. analyzed data; and M.G.G. and R.A.Y. wrote the paper.

Abbreviations: Pol II, RNA polymerase II; H3-K4, histone H3 lysine 4; miRNA, microRNA; IP, immunoprecipitation; ChIP, chromatin IP; CTD, carboxyl-terminal domain.

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